Quinolone and naphthyridone carboxylic acids, zwitterionic salts thereof, and pharmaceutically acceptable salts thereof, are useful as antibacterial agents, and have been prepared according to methods described in, e.g., U.S. Pat. No. 4,738,968 to Matsumoto et al., U.S. Pat. No. 4,382,937 to Matsumoto et al., U.S. Pat. No. 4,382,892 to Hayakawa et al., U.S. Pat. No. 4,571,396 to Hutt et al., U.S. Pat. No. 4,416,884 to Ishikawa et al., U.S. Pat. No. 4,775,668 to Jefson et al., U.S. Pat. No. 5,164,402 to Brighty and U.K. Patent Publication No. 2,191,776 to Toyama Chemical Co. Ltd. Such quinolone and naphthyridone carboxylic acids, and zwitterionic salts thereof, have been obtained (see, e.g., U.S. Pat. No. 5,164,402 to Brighty) by coupling a compound of formula I ##STR1## wherein R.sup.2 is C.sub.1 -C.sub.6 alkyl, especially ethyl or methyl, or hydrogen; A is CH, CF, CCl, COCH.sub.3, CCH.sub.3, CCN or N; Y, when taken independently, is ethyl, t-butyl, vinyl, cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p-difluorophenyl; or A is a carbon atom and is taken together with Y and the carbon and nitrogen atoms to which A and Y are attached to form a five- or six-membered ring which may contain oxygen or a double bond, and which may have methyl or methylene attached to the ring; and W is H, F, Cl, Br, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, amino or NHCH.sub.3 ; with a cyclic compound having an amino group, and having the formula II EQU HR.sup.1 (CH.sub.2).sub.a NHX II
wherein a is 0 or 1; R.sup.1 is a cyclic secondary amino group; and X is a protecting group, such as tertiary-butoxycarbonylamino.
The coupling of a compound of formula I with a compound of formula II results in the displacement of the chloro group from, and the attachment of the secondary amino group to, the 7-carbon atom of the compound of formula I.
Examples of compounds of formula II are 3-azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane (U.S. Pat. No. 5,164,402 to Brighty), and pyrrolidines (U.S. Pat. No. 4,382,937 and U.S. Pat. No. 4,738,968 to Matsumoto et al.), each bearing a protected amino group.
It is necessary that a compound of formula II have a protecting group (in the form of "X") on its primary amino group to prevent the otherwise unprotected primary amino group from competing with the secondary amino group for bond formation with the 7-carbon atom of the compound of formula I. However, the need for such a protecting group adds at least two extra steps to the synthesis of quinolone and naphthyridone carboxylic acids: (1) the addition of the protecting group onto the primary amino group of a compound of formula II prior to reaction with a compound of formula I, and (2) the removal of the protecting group subsequent to reaction with a compound of formula I. These additional steps naturally add to the cost of the synthesis, lengthen the time in which the synthesis can be completed, and limit the time that workers can spend performing other experiments. Accordingly, a process for obtaining quinolone and naphthyridone carboxylic acids that omits the use of protecting groups would be highly desirable and advantageous.
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available as prior art to the present application.